M6A Reader: Epitranscriptome Target Prediction and Functional Characterization of N 6-Methyladenosine (m6A) Readers.

Di Zhen,Yuxin Zhang,Yuxuan Wu,Haiqi Xu,Yujiao Tang,Zhen Wei,Jia Meng,Kunqi Chen,Bowen Song

doi:10.3389/fcell.2020.00741

Di Zhen, Yuxin Zhang + Show 7 more

Open Access

https://doi.org/10.3389/fcell.2020.00741

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Abstract

N6-methyladenosine (m6A) is the most abundant post-transcriptional modification in mRNA, and regulates critical biological functions via m6A reader proteins that bind to m6A-containing transcripts. There exist multiple m6A reader proteins in the human genome, but their respective binding specificity and functional relevance under different biological contexts are not yet fully understood due to the limitation of experimental approaches. An in silico study was devised to unveil the target specificity and regulatory functions of different m6A readers. We established a support vector machine-based computational framework to predict the epitranscriptome-wide targets of six m6A reader proteins (YTHDF1-3, YTHDC1-2, and EIF3A) based on 58 genomic features as well as the conventional sequence-derived features. Our model achieved an average AUC of 0.981 and 0.893 under the full-transcript and mature mRNA model, respectively, marking a substantial improvement in accuracy compared to the sequence encoding schemes tested. Additionally, the distinct biological characteristics of each individual m6A reader were explored via the distribution, conservation, Gene Ontology enrichment, cellular components and molecular functions of their target m6A sites. A web server was constructed for predicting the putative binding readers of m6A sites to serve the research community, and is freely accessible at: http://m6areader.rnamd.com.

Highlights

In the exploration of RNA epigenetics, more than 150 types of RNA modification have been identified (Boccaletto et al, 2018)
A total of 16,664 m6A sites located on 4,722 different genes reported by four experiments were considered as the target sites of YTHDC1, and 1,234 sites on 275 genes identified by two experiments were considered as the target sites for YTHDC2
Combining incremental feature selection (IFS) and Support Vector Machine (SVM), Area under the ROC Curve (AUC) value of 5-fold cross-validation were obtained for each feature subset

Summary

Introduction

In the exploration of RNA epigenetics, more than 150 types of RNA modification have been identified (Boccaletto et al, 2018). Similar to other epigenetic modifications, m6A is thought to be dynamic and reversible (Song et al, 2019). It can be installed by methyltransferase (writers) or removed by demethylase (erasers). This internal modification attracts specific binding proteins, namely readers, which bind selectively to m6A-containing transcripts (Liao et al, 2018). The most widely studied readers are YT521-B homology (YTH) family of proteins, which possess the evolutionarily conserved YTH domain that recognizes m6A mark. Five m6A readers were reported to have the YTH domain, namely YTHDF1,2,3 and YTHDC1,2. The YTH domain is not indispensable for m6A readers, a subunit of translation initiation complex factor EIF3 complex, called EIF3A, was reported as an m6A reader lacking YTH domain (Meyer et al, 2015)

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